The invention relates to the field of vaccine adjuvants. In particular, the invention relates to the use of an amphipathic compound for the manufacture of a vaccine composition intended for nonresponding subjects.
It is known that, when a population of individuals is vaccinated against a disease, a number of them do not xe2x80x9crespondxe2x80x9d to the vaccination, that is to say that their immune system does not appear to react to the antigen administered. This problem is substantial to a greater or lesser degree depending on the diseases and the populations involved, but vaccine manufacturers are still trying to reduce, for each of the vaccines which they make available to doctors, the number of subjects likely to be xe2x80x9cnonrespondersxe2x80x9d. This problem is considered particularly for vaccines comprising purified antigens such as subunit vaccines produced by genetic engineering and in particular the hepatitis vaccine; however, while a number of amphipathic compounds, and in particular 3-xcex2-[N-(Nxe2x80x2,Nxe2x80x2-dimethylaminoethane)carbamoyl]cholesterol, commonly called DC-chol, are known which make it possible to increase the immune response in subjects who are already xe2x80x9crespondersxe2x80x9d, and are therefore considered to be good vaccine adjuvants, it is more difficult to find means of overcoming the problem of nonresponders, all the more so since all the reasons why an individual is a nonresponder have not yet been clearly identified. The research studies carried out in this field have shown that it was not possible to extrapolate the results obtained with adjuvants capable of increasing the immune response in xe2x80x9crespondingxe2x80x9d subjects to the xe2x80x9cnonrespondingxe2x80x9d subjects, given that some good adjuvants in responding subjects are found to have no effect in nonresponding subjects.
The aim of the invention is therefore to provide an improved vaccine as regards the level of seroconversion which it makes possible to obtain. For that, the invention proposes the use of an amphipathic compound for the preparation of a vaccine composition comprising at least one subunit antigen intended to be administered to target populations comprising individuals who are xe2x80x9cnonrespondersxe2x80x9d to said antigen.
According to the invention, the amphipathic compounds are cholesterol derivatives attached to a quaternary ammonium or to a protonable amine by a carbamoyl bond. These compounds, such as DC-chol, can exist in the basic form, in the salt form or alternatively, and this is the most frequent case, in both of the two forms in equilibrium in a mixture, the shifting of the equilibrium toward either form depending on the composition of the mixture and in particular on its pH. One of the particularly advantageous amphipathic compounds for the purposes of the invention is DC-chol which may be obtained from cholesteryl chloroformate and from N,N-dimethylethylenediamine, according to the method described in patent U.S. Pat. No. 5,283,185 or, preferably, according to the method described in Example 8 of patent application WO 96/40067. The 2 forms of DC-chol generally in equilibrium are illustrated in FIG. 1. It is also possible to use a product obtained by reacting cholesteryl chloroformate and N,N,N-trimethylethylenediamine.
The amphipathic compounds may exist in the form of a dispersion in an aqueous or oily medium.
The vaccine composition which needs to be modified so as to reduce the number of individuals who are nonresponders thereto is a composition comprising at least one highly purified subunit antigen. Indeed, such antigens are in general less immunogenic than less purified preparations obtained from whole microorganisms and may therefore lead to a higher proportion of nonresponders. In particular, according to the invention, the number of nonresponders to the hepatitis B antigen is reduced. This may be any hepatitis B antigen, and in particular an antigen containing the S and pre-S2 regions, such as the antigen described in patent EP 0 273 811.
To assess the efficacy of the subject of the invention, animal models are used. The results obtained with the compounds according to the invention and those obtained with conventional prior art adjuvants are thus compared in parallel on a group of nonsyngenic OF 1 mice which, like the human population, is composed of both responding subjects and nonresponding subjects. Comparison of the number of subjects to have undergone seroconversion in each of the groups makes it possible to assess the benefit of the subject of the invention.
Another test may be performed on mice belonging to a strain described as being a nonresponder to the antigen considered, such as the B10.MH2f mice for the hepatitis B antigen. Comparison of the results obtained in each of the groups makes it possible to assess the efficacy of the subject of the invention.
The vaccine composition according to the invention may be provided in liquid form or in freeze-dried form.
The vaccine composition according to the invention may be a monovalent composition (that is to say which is intended to protect against only one disease) or a multivalent composition (which protects against several diseases).
It may comprise, in addition to the adjuvant according to the invention, one or more other adjuvants conventionally intended to increase the response of the immune system, whether this is a humoral-type or a cellular-type response, or a combination of both types.
Conventionally, the vaccine composition according to the invention may comprise, in addition, all the ingredients usually present in vaccines: stabilizer, preservative, cryoprotectant and the like. This composition may be provided in liquid form or in freeze-dried form.